Mast cells, known as conductor cells in allergic inflammation, are activated by numerous stimuli including antigens and produce various inflammatory mediators.
Prostaglandin D2 (PGD2) is a major prostanoid produced by activated mast cells. Some reports showed that antigen challenge induces remarkable PGD2 production in the airway of asthmatic patient (New England Journal of Medicine, 1986, 315 (13), pp. 800-804), in the nasal mucosa of the allergic rhinitis patient or in the skin of the atopic dermatitis patient (Journal of Immunology, 1991, 146(2), pp. 671-676.).
Fujitani et al. reported that overexpression of PGD synthase in transgenic mice which PGD2 production is increased leads to enhanced airway eosinophil infiltration and Th2 cytokine production in an antigen induced asthma model (Journal of Immunology, 2002, 168(1), pp. 443-449.). In this way, it is thought that PGD2 is closely related to the pathogenesis of the allergic diseases and their exacerbation.
At first, it was thought that most of the biological actions of PGD2 are mediated through the classical PGD2 receptor DP. However, several actions of PGD2 such as eosinophil activation could not be mimicked by BW245C, a selective DP agonist (Investigate Opthlmology & Visual Science, 1990, 1, pp. 138-146.), and proposed that eosinophils are activated by PGD2 through a novel PGD2 receptor (Blood, 2001, 98(6), pp. 1942-1948). Around the same time, Hirai et al. reported that PGD2 induces chemotaxis of Th2 cells, eosinophils and basophils through Chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) (The Journal of Experimental Medicine, 2001, 193(2), pp. 255-261). Originally, CRTH2 was cloned as an orphan chemoattractant-like receptor and the ligand activity was found in conditioned medium of activated mast cells. Nagata et al. showed that CRTH2 is selectively expressed by Th2 cells, eosinophils and basophils which are inflammatory cells related to allergic reactions (Journal of Immunology, 1999, 162(3), pp. 1278-1286, FEBS Letter, 1999, 459 (2), pp. 195-199).
The functions of CRTH2 are reported that induction of cell migration (on Th2 cells, eosinophils or basophils), up-regulation of adhesion molecules (on Th2 cells or eosinophils), promotion of Th2 cytokine production (on Th2 cells), from previous researches using CRTH2/DP agonist and/or antagonist. On the other hand, the functions of DP are reported that inhibition of platelet aggregation, vasodilatation, relaxation of smooth muscle, inhibition of cell migration (on eosinophils or dendritic cells), induction of apoptosis (on eosinophils), induction of sleep. Therefore, it is thought that PGD2 induces local vasodilation through DP which enhances vascular permeability, and induces inflammatory cells infiltration and activation through CRTH2. Thus, the PGD2-CRTH2 system plays a significant role in allergic inflammation (Prostaglandins Leukotrienes & Essential Fatty Acids, 2003, 69 (2-3), pp. 169-177, Natural Review Drug Discovery, 2007, 6(4), pp. 313-325).
In conclusion, PGD2, the major prostanoid produced by mast cells, activates inflammatory cells including Th2 cells, eosinophils and basophils and play an important roll for the allergic inflammation through CRTH2. Therefore, CRTH2 antagonist is expected to be developed as an anti-inflammatory medicine for treatment of patients with allergic diseases.
Benzhydryl-pyridazinone and benzhydryl-pyridone compounds are disclosed in International publication No. WO 95/24393 and Bioorganic & Medicinal Chemistry Letters, 2000, 10(24), pp. 2787-2790.

The publications disclosed that the compounds of each publications are identified as non prostanoid PGI2 agonist, and that these compounds show inhibitory activity on platelet aggregation, a vasodilating activity, an antihypertensive, activity and the like, and that the compounds are useful as medicaments for the therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension and the like. However each of the publications does not mention or give suggestions on allergic reaction.